1. Field of the Invention
This invention relates to compounds which are bradykinin receptor antagonists, pharmaceutical compositions and methods for using these compounds to antagonize the effects of bradykinin in mammals, including humans. More particularly, the invention relates to the substitution of the L-Pro at position 7 with D-hydroxyproline ether or thioether compounds and its intermediate product which convert bradykinin agonists into antagonists and also includes additional modifications at other positions within the 7-position modified bradykinin antagonist which confer increased antagonist potency, resistance to enzymatic degradation, and/or tissue specificity on the D-amino acid-containing bradykinin sequence.
2. Description of the Prior Art
Bradykinin (BK) is a nonapeptide generated as a result of the activity of kallikreins, a group of proteolytic enzymes present in most tissues and body fluids, on kininogens. Once released, kinins produce many physiological responses, including pain and hyperanalgesia by stimulating C- and A-fibers in the periphery. There is also considerable evidence that kinins contribute to the inflammatory response.
Bradykinin, and its physiologically important related peptides kallidin (Lys-bradykinin) and Met-Lys-bradykinin, exhibit physiological actions which qualify them as mediators of inflammatory reactions, hypotensive states, and pain. Bradykinin is overproduced in pathological conditions such as septic shock, anaphylaxis, rhinitis, asthma, inflammatory bowel disease, and certain other conditions including acute pancreatitis, post-gastrectomy dumping syndrome, carcinoid syndrome, migraine, and angioneurotic edema. The production of bradykinin from the plasma results in pain at the site of the pathological condition, and the overproduction intensifies the pain directly or via bradykinin-induced activation of the arachidonic acid pathway which produces prostaglandins and leukotrienes, the more distal and actual mediators of inflammation.
In addition to its analgesic and proinflammatory effects, bradykinin is a vasodilator. Because of its ability to lower blood pressure, bradykinin has been implicated in the pathogenesis of several shock syndromes, particularly septic or endotoxic shock. Bradykinin is also a potent bronchoconstrictor in animals and asthmatic subjects and it has been implicated as a contributor to the pathogenesis of airway inflammatory conditions such as allergic asthma and rhinitis.
Thus, a bradykinin inhibitor or bradykinin receptor antagonist is expected to possess a number of desirable biological effects in the treatment, for example, of inflammation, septic shock, asthma, burn pain, rhinitis, and allergy.
The search for understanding the mechanism of action of bradykinin, which is essential for the development of useful tools for diagnostic use, and for the development of therapeutic agents aimed at alleviating the intense pain caused by the production and overproduction of bradykinin, has been hindered by the lack of specific sequence-related competitive antagonists of bradykinin.
Several non-peptide, non-specific and non-selective antagonists of one or more of the biological activities of bradykinin have been described among compounds as diverse as analgesics and anti-inflammatory substances, which act via the prostaglandin system and not directly on bradykinin receptors. These are antihistamines; bradykinin-antibodies; benzodiazepine derivatives; high molecular weight ethylene oxide polymers; gallic acid esters; and serotonin inhibitors. None of these compounds or classes of compounds specifically inhibit the effects of bradykinin.
Heptyl esters of various amino acid-containing substances, such as single basic amino acids, the dipeptide Phe-Gly, and analogs of C-terminal peptide fragments of bradykinin (i.e., Pro-Phe-Arg) have been reported as anti-bradykinin substances. When tested in bradykinin assay systems, they prove to be weak partial agonists/antagonists, depending on the dose, with little specificity for inhibiting bradykinin action.
Preparations of damaged vascular tissue have been reported to respond to bradykinin analogs which lack the C-terminal arginine residue, but not to bradykinin itself, and analogs of these des-Arg(9)-bradykinins have been developed as antagonists for the non-physiological activity of bradykinin. These antagonists have no significant bradykinin-like agonist effects, nor any antagonist effect on any of the physiologically significant kinin-responding systems. Furthermore, several bradykinin analogs containing the O-methyl ether of Tyr residues at positions 5 and/or 8 have been reported to produce mixed agonist/antagonist activity on isolated uteri of galactosemic rats, but not on normal rats.
Other changes in the bradykinin molecule have been additions of amino acids at the N-terminal end which affect the rate of enzymatic degradation of bradykinin in vivo.
It has been reported that the half life of bradykinin in the systemic circulation is less than 30 seconds. Bradykinin appears to be completely destroyed (98-99% destruction) on a single passage through the pulmonary circulation as determined in an anesthetized rat by measuring the depressor effects of an agonist following intra-aortic (IA) (bypassing the pulmonary circulation) and intravenous (IV) administration. Resistance of bradykinin agonists to pulmonary kininase destruction in vivo also appears promoted by addition of single (i.e., D-Arg-, D-Lys-, Lys-) and double (D-Lys-Lys-) basic amino acid residues to the N-terminal of the bradykinin sequence. The addition of the dipeptide Lysxe2x80x94Lys to the N-terminal of bradykinin agonists has been reported to confer complete resistance to in vivo destruction on initial passage through the pulmonary circulation.
Several research groups have prepared bradykinin receptor antagonists. Stewart and Vavrek in U.S. Pat. No. 4,801,613, (which reference is incorporated in its entirety herein) disclose a series of bradykinin antagonists wherein the L-Pro at the 7-position of the peptide hormone bradykinin or other substituted analogs of bradykinin is substituted with an aromatic amino acid of the D-configuration which converts bradykinin agonists into bradykinin antagonists. The analogs produced are useful in treating conditions and diseases of a mammal and human in which an excess of bradykinin or related kinins are produced or injected as by insect bites into the body. The specific L-Pro substitutions are selected from the group consisting of D-Nal, D-PNF, D-Phe, D-Tyr, D-Pal, D-OMT, D-Thi, D-Ala, D-Trp, D-His, D-Homo-Phe, D-Phe, pCl-D-Phe (CDF), D-Phg, D-Val, D-Ile, D-Leu, and MDY.
In U.S. Pat. No. 4,693,993, also to Stewart and Vavrek, additional L-Pro substitution materials are disclosed.
Copending application Ser. No. 08/167,051, filed Dec. 16, 1993, which is a continuation of application Ser. No. 07/866,385 filed Apr. 14, 1992, which in turn was a continuation-in-part of Ser. No. 07/687,950 filed Apr. 19, 1991, discloses and claims additional L-Pro substitution materials with hydroxyproline ether and thioether compounds.
U.S. Pat. No. 4,242,329 to Claeson et al. disclose the formation of Bradykinin-inhibiting tripeptide derivatives. A process for producing said tripeptide derivatives by synthesis and purification methods which are known in the peptide chemistry is also disclosed as well as pharmaceutical preparations comprising the tripeptide derivative.
Published European Patent Applications No. 0 413 277 A1 and 0 370 453 AZ disclose bradykinin antagonists.
The present invention resides in the discovery that the novel compounds identified below, are potent bradykinin receptor antagonists. The compounds are useful in the treatment of various diseases including inflammatory disorders, asthma, septic shock, and burn pain. Included in the invention are pharmaceutical compositions containing the inventive compounds and methods of using the compounds as bradykinin receptor antagonists.
More particularly, the invention relates to the modification of the sequence of the mammalian peptide hormone bradykinin (Arg Pro Pro Gly Phe Ser Pro Phe Arg), SEQ ID NO 1, and pharmaceutically acceptable salts thereof, at the Pro residue at position 7 in a unique manner which produces sequence-related analogues that act as specific and competitive inhibitors of the biological activities of bradykinin. The invention specifically relates to the substitution of the L-Pro at position 7 with a material having the D-configuration (*) and the formula: 
wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2; and pharmaceutically acceptable salts thereof.
More specifically, the invention relates to the formation of peptides having the formula:
N-A-B-C-D-E-F-G-H-I-J-Cn
wherein N is hydrogen;
A and B are independently selected from the group consisting of L-Arg, D-Arg, D-Gln, L-Gln, D-Asn, L-Asn, N-xcex5-acetyl-D-lysine, xcex5-acetyl-L-lysine, NG-p-tosyl-Arg, NG-nitro-Arg, Lysxe2x80x94Lys, acetyl-D-Arg, L-Citrulline, L-Lys, Sar, and D-Lys;
C and D are a direct bond or are independently selected from the group consisting of Pro, dehydroPro, 4Hyp, Tic, Aoc, L-azetidine-2-carboxylic acid, Eac, Gly, Thz, Oic, Ala, and Aib;
E is a direct bond or is selected from the group consisting of Gly, Ala, Thr, and Ser;
F is selected from the group consisting of Phe, Thi, Leu, Ile, Tic, Oic, homoPhe, phenylGly, xcex2-cyclohexylalanine, Nal, and Val;
G is a direct bond or is selected from the group consisting of Ser, Thr, 4Hyp, Gly, Val, and Ala;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
I is selected from the group consisting of Oic, Aoc, Thz, Tic, L-indoline-2-carboxylic acid, octahydro-1H-isoindole-1-carboxylic acid, pipecolinic acid, Pro, 4Hyp, azetidine-2-carboxylic acid, Aib, Leu, Ile, Val, Thi, Phe, homoPhe, and compounds of the following formula: 
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula RNHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
J is selected from the group consisting of Arg, Orn, Asn, Gln, N-xcex5-acetyl-Lys, N-xcex4-acetyl-Orn, and Lys;
Cn is a hydroxyl group or a C-terminal extension is selected from the group consisting of amide, alkoxy group, an acidic, basic or neutral aliphatic, aromatic, cyclic amino acid residue of the D- or L-configuration, and a peptide extension composed of D- or L-amino acids; and pharmaceutically acceptable salts thereof.
A particularly preferred material is a peptide wherein:
N is hydrogen;
A and B are independently selected from the group consisting of L-Arg, D-Arg, Lysxe2x80x94Lys, Lys;
C and D are independently selected from the group consisting of Pro, dehydroPro, and 4Hyp;
E is Gly;
F is selected from the group consisting of Phe, Thi, Leu, and xcex2-cyclohexylalanine;
G is a direct bond or is selected from the group consisting of Ser and Thr;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
I is selected from the group consisting of Oic, Aoc, Thz, Pro, pipecolinic acid, Leu, Phe, Thi, Tic, and compounds of the formula: 
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
J is selected from the group consisting of Arg and Lys;
Cn is a hydroxyl group;
and pharmaceutically acceptable salts thereof.
Another preferred material is a peptide wherein:
N is hydrogen;
A is D-Arg;
B is Arg;
C is Pro;
D is selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Phe, Leu, and Thi;
G is a direct bond or is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, isobutyl, cyclohexylmethyl, allyl, methallyl, prenyl, benzyl, phenyl, nitrophenyl, napthal, chlorophenyl, 4-methylphenyl, 3-phenylpropyl, phenylpropyl, and methylbutyl, and where X is SOn or oxygen, and n=0, 1, or 2;
I is selected from the group consisting of Oic, Aoc, Thz, Tic, and compounds of the formula: 
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, isobutyl, cyclohexylmethyl, allyl, methallyl, prenyl, benzyl, phenyl, 4-chlorophenyl, 4-methylphenyl, and phenylcarbamoyl and where X is either SOn or oxygen, and n=0, 1, or 2;
J is Arg;
Cn is a hydroxyl group;
and pharmaceutically acceptable salts thereof.
The present invention also includes the intermediate compound having the D-trans formula: 
Preferred peptides according to the invention include the following nonlimiting materials:
Hyp Pro Alkyl Ethers and Substituted Alkyl Ethers
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-hydroxyproline cis methyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-hydroxyproline cis propyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-hydroxyproline cis ethyl ether)-Oic Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-Aoc-Arg
Proxe2x80x94Pro Alkyl Ethers
Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-Tic-Arg
D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-Tic-Arg
D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-Tic-Arg
D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-Oic-Arg
D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-Oic-Arg
D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-Oic-Arg
D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-Aoc-Arg
D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-Aoc-Arg
D-Arg-Arg-Pro-Pro-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-Aoc-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-Tic-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-Tic-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-Tic-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-Oic-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-Oic-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-Oic-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-Aoc-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-Aoc-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-Aoc-Arg
Arylalkyl Ethers
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-hydroxyproline trans 3xe2x80x2-phenylpropyl ether)-Oic-Arg
Thioalkyl Ethers
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiomethylproline)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thioethylproline)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiopropylproline)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiomethylproline)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thioethylproline)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiopropylproline)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiomethylproline)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thioethylproline)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiopropylproline)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiomethylproline)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thioethylproline)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiopropylproline)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiomethylproline)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thioethylproline)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiopropylproline)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiomethylproline)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thioethylproline)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiopropylproline)-Aoc-Arg
Thioaryl Ethers and Substituted Aryl Ethers
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiophenylproline)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiophenylproline)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-trans thiophenylproline)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiophenylproline)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiophenylproline)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-trans thiophenylproline)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-hydroxyproline trans 4xe2x80x2-nitrophenyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-hydroxyproline trans napthal thioether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-hydroxyproline cis phenyl thioether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-hydroxyproline trans 2xe2x80x2-nitrophenyl ether)-Oic-Arg
D-Arg-Arg-Pro-Pro-Gly-Phe-Ser-(D-4-hydroxyproline trans phenyl thioether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-hydroxyproline trans p-chlorophenyl thioether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-hydroxyproline trans p-methylphenyl thioether)-Oic-Arg
Allyl Ethers
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans allyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans allyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans allyl ether)-Aoc-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans allyl ether)-Tic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans allyl ether)-Oic-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans allyl ether)-Aoc-Arg
Hydroxyproline Ethers Hydroxyproline Ethers
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-(L-4-Hydroxyproline cis methyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-(L-4-Hydroxyproline cis methyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-(L-4-Hydroxyproline cis methyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-(L-4-Hydroxyproline cis ethyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-(L-4-Hydroxyproline cis ethyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-(L-4-Hydroxyproline cis ethyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans methyl ether)-(L-4-Hydroxyproline cis propyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans ethyl ether)-(L-4-Hydroxyproline cis propyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-(L-4-Hydroxyproline cis propyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-(L-4-Hydroxyproline cis methyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-(L-4-Hydroxyproline cis methyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-(L-4-Hydroxyproline cis methyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-(L-4-Hydroxyproline cis ethyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-(L-4-Hydroxyproline cis ethyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-(L-4-Hydroxyproline cis ethyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans methyl ether)-(L-4-Hydroxyproline cis propyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans ethyl ether)-(L-4-Hydroxyproline cis propyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Phe-Ser-(D-4-Hydroxyproline trans propyl ether)-(L-4-Hydroxyproline cis propyl ether)-Arg
D-Arg-Arg-Pro-4Hyp-Gly-Thi-Ser-(D-4-Hydroxyproline trans propyl ether)-(L-4-Hydroxyproline trans methyl ether)-Arg
Another embodiment of the invention involves a pharmaceutical composition useful as a bradykinin receptor antagonist comprising a pharmaceutical carrier and an effective amount of the novel bradykinin-type peptide. The invention also involves a process for antagonizing bradykinin receptor activity in mammals which comprises: administering to a subject an effective amount of the novel compound to antagonize bradykinin receptor activity.
A further embodiment involves a pharmaceutical preparation for treating local pain and inflammation from burns, wounds, cuts, rashes and other such trauma, and pathological conditions caused by the production of bradykinin or related kinins by an animal which comprises administering an effective amount of the novel peptide sufficient to antagonize bradykinin with a suitable pharmaceutical carrier. Another aspect of this invention involves a process for treating local pain and inflammation which comprises administering an effective amount of the pharmaceutical preparation to an animal in need thereof.
The present compounds which are bradykinin receptor antagonists have the following formula:
N-A-B-C-D-E-F-G-H-I-J-Cn
wherein N is hydrogen;
A and B are independently selected from the group consisting of L-Arg, D-Arg, D-Gln, L-Gln, D-Asn, L-Asn, Nxcex5E-acetyl-D-lysine, xcex5-acetyl-L-lysine, NG-p-tosyl-Arg, NG-nitro-Arg, Lysxe2x80x94Lys, acetyl-D-Arg, L-Citrulline, L-Lys, Sar, and D-Lys;
C and D are a direct bond or are independently selected from the group consisting of Pro, dehydroPro, 4Hyp, Tic, Aoc, Ala, L-azetidine-2-carboxylic acid, Eac, Gly, Thz, Oic, and Aib;
E is a direct bond or is selected from the group consisting of Gly, Ala, Thr, and Ser;
F is selected from the group consisting of Phe, Thi, Leu, Ile, Tic, Oic, homoPhe, phenylGly, xcex2-cyclohexylalanine Nal, and Val;
G is a direct bond or is selected from the group consisting of Ser, Thr, 4Hyp, Gly, Val, and Ala;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
I is selected from the group consisting of Oic, Aoc, Thz, Tic, L-indoline-2-carboxylic acid, octahydro-1H-isoindole-1-carboxylic acid, pipecolinic acid, Pro, 4Hyp, azetidine-2-carboxylic acid, Aib, Leu, Ile, Val, Thi, Phe, homoPhe, and compounds of the formula: 
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
J is selected from the group consisting of Arg, Orn, Asn, Gln, N-xcex5-acetyl-Lys, N-xcex4-acetyl-Orn, and Lys;
Cn is a hydroxyl group a C-terminal extension selected from the group consisting of amide, alkoxy group, an acidic, basic or neutral aliphatic aromatic, and cyclic amino acid residue of the D- or L-configuration, and a peptide extension composed of D- or L-amino acids; and pharmaceutically acceptable salts thereof.
Formula 2
Preferred compounds are those in which:
N is hydrogen;
A and B are independently selected from the group consisting of L-Arg, D-Arg, Lysxe2x80x94Lys, Lys;
C and D are independently selected from the group consisting of Pro, dehydroPro, and 4Hyp;
E is Gly;
F is selected from the group consisting of Phe, Thi, Leu, and xcex2-cyclohexylalanine;
G is a direct bond or is selected from the group consisting of Ser and Thr;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
I is selected from the group consisting of Oic, Aoc, Thz, Pro, pipecolinic acid, Leu, Phe, Thi, Tic, and compounds of the formula: 
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
J is selected from the group consisting of Arg and Lys;
Cn is hydroxyl;
and pharmaceutically acceptably salts thereof.
Formula 3
Most preferred are compounds wherein:
N is hydrogen;
A is D-Arg;
B is Arg;
C is Pro;
D is selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Phe, Leu, and Thi; G is a direct bond or is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, isobutyl, cyclohexylmethyl, allyl, methallyl, prenyl, benzyl, phenyl, nitrophenyl, napthal, chlorophenyl, methylphenyl, phenylpropyl, and methylbutyl, and where X is either SOn or oxygen, and n=0, 1, or 2;
I is selected from the group consisting of Oic, Aoc, Thz, Tic, and compounds of the formula: 
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, isobutyl, cyclohexylmethyl, allyl, methallyl, prenyl, benzyl, phenyl, and phenylcarbamoyl, and where X is either SOn or oxygen, and n=0, 1, or 2;
J is Arg;
Cn is a hydroxyl group;
and pharmaceutically acceptable salts thereof.
Formula 4
The inventive compositions also include the following preferred formulations:
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
I is selected from the group consisting of Tic, Aoc, and Oic;
J is Arg;
CN is a hydroxyl group;
and pharmaceutically acceptable salts thereof.
Formula 5
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Phe and Thi;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is selected from the group consisting of C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
I is Oic;
J is Arg;
CN is a hydroxyl group;
and pharmaceutically acceptable salts thereof.
Formula 6
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, phenyl, chlorophenyl, naphthyl, methylphenyl, and X is sulfur;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 7
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, 3-phenylpropyl, methylbutyl, and phenyl and X is oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 8
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Phe and Thi;
G is a direct bond or is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, chlorophenyl, methylphenyl, phenylpropyl, and phenyl and X is sulfur or oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 9
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is methyl and X is oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 10
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is ethyl and X is oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 11
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is propyl and X is oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 12
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is phenyl and X is oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 13
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is allyl and X is oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 14
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Thi and Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is 3-methylbutyl and X is oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 15
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Thi and Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is 3-phenylpropyl and X is oxygen;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 16
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is methyl and X is sulfur;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 17
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is ethyl and X is sulfur;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 18
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is propyl and X is sulfur;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 19
A is D-Arg;
B is Arg;;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Thi and Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is phenyl and X is sulfur;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 20
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Thi and Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is p-chlorophenyl and X is sulfur;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 21
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is selected from the group consisting of Thi and Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is p-methylphenyl and X is sulfur;
I is Oic;
J is Arg;
and pharmaceutically acceptable salts thereof.
Formula 22
A is D-Arg;
B is Arg;
C and D are independently selected from the group consisting of Pro and 4Hyp;
E is Gly;
F is Phe;
G is Ser;
H is a compound of the D-configuration having the formula: 
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, allyl, methallyl, benzyl, phenyl, nitrophenyl, napthal, chlorophenyl, methylphenyl, phenylpropyl, methylbutyl and phenyl, and where X is either SOn or oxygen, and n=0, 1, or 2;
I is a compound of the formula: 
xe2x80x83wherein R is selected from the group consisting of methyl, ethyl, propyl, allyl, methallyl, benzyl, methylphenyl, chlorophenyl, phenylpropyl, and phenyl and where X is either SOn or oxygen, and n=0, 1, or 2;
J is Arg;
and pharmaceutically acceptable salt thereof.
The invention also contemplates the preparation of an intermediate chemical entity as well as its use to prepare a bradykinin antagonist peptide. The intermediate is in the D-configuration, either the cis or trans structure, preferably trans has formula: 
wherein R is-selected from the group consisting of, hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C8 alkenyl, C3-C8 cycloalkyl, C3-C8 cycloalkyl substituted C1-C6 alkyl, an aryl group, a substituted aryl group, an arylalkyl group, and a group of the formula R1NHC(o)xe2x80x94 where R1 is C1-C6 alkyl or aryl, and where X is either SOn or oxygen, and n=0, 1, or 2;
R2 is selected from the group consisting of hydrogen, C1-C6 alkyl, C2-C8 alkenyl, an aryl group, and an arylalkyl group;
R3 is H or a suitable amine protecting group; provided that when R is hydrogen, R2 is a C1-C6 alkyl group.
As used in the specification and claims, xe2x80x9calkylxe2x80x9d is a paraffinic hydrocarbon group which may be derived from an alkane by dropping one hydrogen from the formula, such as methyl, ethyl, propyl, isopropyl, butyl, and so forth; xe2x80x9csubstituted C1-C6 alkylxe2x80x9d is a branched alkyl, such as methyl butyl; xe2x80x9carylxe2x80x9d is an aromatic ring compound such as benzene, phenyl, naphthyl; xe2x80x9csubstituted arylxe2x80x9d is a substituted aromatic ring, such as nitro substitution, or halogen substitution; and xe2x80x9caralkylxe2x80x9d is an aryl being attached through an alkyl chain, straight or branched, containing from one through six carbons, such as a phenylpropyl group. A xe2x80x9cdirect bondxe2x80x9d is a bond which replaces a particular amino acid compound between adjacent amino acids and which amino acid may also be indicated to be absent by the term xe2x80x9cnullxe2x80x9d. The phrase xe2x80x9ca suitable amine protecting groupxe2x80x9d is a group, such as BOC (t-butyloxy-carbonyl-) protecting group which protects the amine moiety from reaction and which can be removed under mild conditions so as not to affect the rest of the molecule.
Exemplary Boc protected amino acids include the following nonlimiting materials:
N-Boc-L-cis-4-methoxyproline;
N-Boc-L-cis-4-(n-propoxy)proline;
N-Boc-L-trans-4-methoxyproline;
N-Boc-L-trans-4-(n-propoxy)proline;
N-Boc-L-trans-4-ethoxyproline;
N-Boc-D-trans-4-phenylthioproline;
N-Boc-D-trans-4-methoxyproline;
N-Boc-L-trans-4-cyclohexylmethoxyproline;
N-Boc-D-trans-4-(3-methylbutoxy)proline;
N-Boc-D-trans-4-(3-phenylpropoxy)proline;
N-Boc-D-trans-4-(p-chlorophenylthio)proline;
N-Boc-D-trans-4-(2-naphthalenethio)proline;
N-Boc-D-trans-4-hydroxyproline methyl ester;
N-Boc-D-trans-4-(n-propoxy)proline;
N-Boc-D-trans-4-ethoxyproline;
N-Boc-L-trans-4-phenylthioproline;
N-Boc-L-trans-4-phenoxyproline;
N-Boc-D-trans-4-(2-nitrophenoxy)proline;
N-Boc-D-cis-4-phenylthioproline;
N-Boc-D-trans-4-(4-nitrophenoxy)proline.
N-Boc-L-trans-4-ethoxyproline
N-Boc-D-trans-4-(p-methylphenylthio)proline
N-Boc-L-cis-4-ethoxyproline
N-Boc-L-trans-4-O-phenylcarbamoylproline
Definitions of the amino acid abbreviations used herein are as follows:
Arg is arginine; Ala is alanine; Aib is 2-aminoisobutyric acid; Aoc is (S,S,S)-2-azabicyclo[3.3.0]octane-3-carboxylic acid; Asn is asparagine; Eac is xcex5-aminocaproic acid; Gln is glutamine; Gly is glycine; Ile is isoleucine; Leu is leucine; Lys is lysine; Met is methionine; Nal is beta-2-naphthylalanine; Orn is ornithine; Pro is proline; dehydroPro is 3,4-dehydroproline; homoPhe is homophenylalanine; 4Hyp is 4-hydroxyproline; Ser is serine; Sar is sarcosine; Thi is beta-2-thienylalanine; Thr is threonine; Thz is thiazolidine-4-carboxylic acid; Phe is phenylalanine; phenylGly is 2-phenylglycine; Tic is tetrahydroisoquinoline-3-carboxylic acid; Oic is (2S, 3aS, 7aS)-octahydro-1H-indole-2-carboxylic acid; Val is valine. Further more, prenyl is a 3-methyl-2-butenyl radical.
Aoc can be prepared by the method of V. Teetz, R. Geiger and H. Gaul, Tetrahedron Lett. (1984), 4479. Tic can be prepared by the method of K. Hayashi, Y. Ozaki, K. Nunami and N. Yoneda, Chem. Pharm. Bull. (1983) 31, 312.
All amino acids residues, except Gly, and Sar, described in the specification are preferably of the L-configuration unless otherwise specified. It would be recognized, however, that the 7 position must always be the D-configuration whereas the hydroxyproline ethers and thioethers of position 8 may be either in the D- or L-configuration. The symbols and abbreviations used for amino acids, their derivatives and protecting groups, and peptides and their salts are those customarily used in peptide chemistry. (See Biochem. J. (1972), 126, 773), which Journal reference is hereby incorporated by reference).
Table I shows the general location of the amino acid groups as used herein.
The synthesis of the peptides of this invention including derivation, activation, and coupling of protected amino acid residues, and their purification, and the analytical methods for determining identity and purity are included in the general body of knowledge of peptide chemistry, as described in Houben Weyl Methoden der Organischen Chemie, (1974), Vol. 16, parts I and II for solution-phase synthesis, and in Solid Phase Peptide Synthesis, (1984), by Stewart and Young for synthesis by the solid-phase method of Merrifield.
Any chemist skilled in the art of peptide synthesis can synthesize the peptides of this invention by standard solution methods or by manual or automated solid phase methods.
The appropriate hydroxyproline substituents used in the 7-position are prepared by the process described in the Examples and depicted in the sequences shown below. The starting materials are commercially available and can be prepared by known procedures. Both the cis and trans stereoisomers can be prepared by these means and are within the scope of the present invention.
In Scheme II M represents sodium, potassium and other useable salts such as alkaline earth metals and alkali metals and X is oxygen or sulfur. 
Alternately, they also can be prepared by the method of Scheme II from commercially available starting materials. 
The preparation of compounds for administration in pharmaceutical preparations may be performed in a variety of methods well known to those skilled in the art. Appropriate pharmaceutically acceptable salts within the scope of the invention are those derived from mineral acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid and sulfuric acid; and organic acids such as tartaric acid, fumaric acid, lactic acid, oxalic acid, ethylsulfonic acid, citric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, giving the hydrochloride, sulfate, phosphate, nitrate, methanesulfonate, tartrate, benzenesulfonate, p-toluensulfonate, and the like, salt, respectively.
The compounds of the invention may contain an asymmetric carbon atom. Thus, the invention includes the individual stereoisomers, and the mixtures thereof. The individual isomers may be prepared or isolated by methods known in the art.
Therapeutic applications of the novel bradykinin antagonists include not only treatment for the production of bradykinin or related kinins by the animal but also the injection of bradykinin related peptides into an animal as a result of bites and stings. Topical application alone or in combination with subcutaneous utilization of the bradykinin antagonists of the invention can be employed to treat the effects of bradykinin-related peptides causing pain, inflammation and swelling.
The therapeutic use of bradykinin antagonists of this invention for other traumatic inflammatory or pathological conditions which are known to be mediated by bradykinin or exacerbated by an overproduction of bradykinin can also be achieved. These conditions include local trauma such as wounds, burns and rashes, angina, arthritis, asthma, allergies, rhinitis, shock, inflammatory bowel disease, low blood pressure, and systemic treatment of pain and inflammation.
In parenteral administration of the novel compounds and compositions of the invention the compounds may be formulated in aqueous injection solutions which may contain antioxidants, buffers, bacteriostats, etc. Extemporaneous injection solutions may be prepared from sterile pills, granules or tablets which may contain diluents, dispersing and surface active agents, binders and lubricants which materials are all well known to the ordinary skilled artisan.
In the case of oral administration, fine powders or granules of the compound may be formulated with diluents and dispersing and surface active agents, and may be prepared in water or in a syrup, in capsules or cachets in the dry state or in a non-aqueous suspension, where a suspending agent may be included. The compounds may also be administered in tablet form along with optional binders and lubricants, or in a suspension in water or syrup or an oil or in a water/oil emulsion and may include flavoring, preserving, suspending, thickening, and emulsifying agents. The granules or tablets for oral administration may be coated and other pharmaceutically acceptable agents and formulations may be utilized which are all known to those skilled in the pharmaceutical art.
Solid or liquid carriers can also be used. Solid carriers include starch, lactose, calcium sulfate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline, and water. Ointments and creams are prepared using various well known hydrophilic and hydrophobic bases. Topical reservoirs suitably are prepared using known polymeric materials such as various acrylic-based polymers selected to provide desired release characteristics. Suppositories are prepared from standard bases such as polyethylene glycol and cocoa butter.
The method of treatment according to this invention comprises administering internally or topically to a subject an effective amount of the active compound. Doses of active compounds in the inventive method and pharmaceutical compositions containing same are an efficacious, nontoxic quantity selected from the range of 0.01 to 100 mg/kg of active compound, preferably 0.1 to 50 mg/kg. Persons skilled in the art using routine clinical testing are able to determine optimum doses for the particular ailment being treated. The desired dose is administered to a subject from 1 to 6 or more times daily, orally, rectally, parenterally, topically, or by inhalation.
The efficacy of the inventive compounds of this invention as bradykinin receptor antagonists can be determined using the bradykinin binding and tissue assays described herein. The results of these assays demonstrate that the novel compounds are potent, selective bradykinin receptor antagonists.
The following examples are illustrative of preferred embodiments of methods of preparation and compounds of the invention and are not to be construed as limiting the invention thereto.